The treatment of acute hematologic malignancies may involve various modalities including intensified chemotherapy, radiation, and blood or bone marrow transplantation. Unfortunately, most patients still succumb to the underlying malignancy or the associated treatment regimens. For example, in patients younger than 60 years of age with acute myelogenous leukemia (AML) and enrolled in clinical studies, overall survival remains less than 40%. In adults with acute lymphoblastic leukemia (ALL) and favorable genetics, similar overall rates of survival are observed.
After achieving leukemic remission, a minority of patients are eligible to receive consolidative high dose therapy (HDT) followed by allogeneic hematopoietic stem and progenitor cell transplantation. In some patients this maneuver results in a cure due to the donor-derived immunological effect of graft versus leukemia. However, these patients unfortunately may also acquire chronic multi-organ damage from graft versus host disease—where the same donor-derived immunological phenomenon is directed at normal tissue. Graft versus host disease has an associated mortality rate of 10-30%. Even so, the majority of adult patients with these acute leukemias are too old to be considered candidates for HDT. The overall survival rate for these patients is less than 10%.
Oncolytic virus-derived therapies are therapies that use viruses either to directly lyse the tumour cells or, if modified, as vectors to infect the tumor cells with genes that encode specific tumor-associated antigens.
Oncolytic viruses (OVs) have been engineered to be dependent upon tumor-specific constitutively activated regulatory pathways. The selective anti-tumor activities of an OV include: direct cytolysis, apoptosis, virus-mediated synctium formation with intra-tumoral viral spread, activation of peri-tumor inflammation and intratumoral coagulation with ischemic necrosis.
Oncolytic virus-derived therapies take advantage of deficiencies of innate immunity which develop in many hematopoietic cancer cells as they acquire their proliferative phenotype. For example, this can involve perturbations in the RAS, DAF, STAT and/or interferon regulatory pathways. OVs have evolved to exploit these immune defects for replication advantage. Infection of a permissive hematopoietic cancer cell with an oncolytic virus results in cell lysis and viral spread to adjacent tumor tissue. Healthy cells with intact innate defenses resist and eliminate the viral threat. Such oncolytic virus-derived therapies may have an impressive therapeutic index, particularly when using a modified virus with deletions in wild-type genes normally responsible for mitigating a cell's anti-viral defense.
Examples of oncolytic virus-derived therapies include vaccines made from virally modified tumor cell lysates. Such vaccines are also known as viral oncolysates and in such vaccines the OV is used to infect and rupture a tumor cell, thereby producing a mixture of cellular debris, which is used to potentially stimulate the immune response in a patient. The cellular debris may be considered to be the antigenic material, while the viruses may be considered to be an adjuvant. Such vaccines are often lysed using mechanical methods in order to produce the mixture of cellular debris.
One problem with cancer vaccines which have been engineered to contain specific tumor antigen peptide(s) is that antigen presentation by antigen presenting cells (APCs) remains inefficient using standard vaccine approaches. APC processing of a single or few tumor peptide(s) likely does not lead to an anti-tumor T-cell response with adequate breadth to significantly impact survival.
Other examples of oncolytic virus-derived therapies include pharmaceutical compositions comprising human leukocytes and replication-competent OVs (see U.S. Pat. No. 7,595,042). The compositions taught in U.S. Pat. No. 7,595,042 use isolated leukocyte cells to protect the virus from neutralizing antibody in a patient, thereby delivering the OV to tumors. This is an advantage over freely injected OVs, which expose the virus to the neutralizing antibody in patients that have generated an immune response, thereby rendering the virus non-infectious.
A review of immunotherapy using acute leukemia cells modified using gene transfer methods to generate functional antigen presenting cells was published in Leukemia (2002) 16, 1974-1983.
Although modest efficacy has been reported using viruses as “oncolysates” in the treatment of solid cancers, non-solid cancers or acute hematologic malignancies such as AML or ALL are difficult to treat with OVs in-situ.